pre zen tare pe esofag baret

8/8/2019 Pre Zen Tare Pe Esofag Baret

1/301


2/301

Barretts Esophagus:Metaplasia and Dysplasia1. Metaplasia - Defn/types

- Pathogenesis- Differential Diagnosis

2. Dysplasia - Incidence/risk factors- Pathologic Features

- Adjunctive Diagnostic tests- Natural History

- Treatment


3/301

Barretts EsophagusDefinition

Columnar metaplasia of esophageal squamous epithelium(any length)

Recognized at endoscopy Goblet cell metaplasia


4/301

Barretts EsophagusGross Types

Long segment (>3cm) Short segment (1-3cm) Ultrashort segment (0-1cm)


5/301


6/301


7/301


8/301


9/301


10/301

Multilayered Epithelium


11/301


12/301

Multilayered Epithelium

1. Hybrid epithelium (squam/colum)- EM, cytokeratins

2. Biologically active3. Phenotypically similar to Barretts

Esophagus4. Highly associated with Barretts

esophagus


13/301


14/301


15/301


16/301

Short (Ultrashort) BE vs.

Chronic Carditis Distinction Important Different clinical, etiologic,

pathologic, outcome, risk of malignancy


17/301


18/301


19/301


20/301


21/301


22/301

Mucin Histochemistry

______________________________________________________ Stain Esoph Cardia

Goblet Non-Goblet Goblet Non-Goblet ______________________________________________________ Alcian blue + + + +(acid mucin

High Iron diamine + + + -(sulphomucin)

_____________________________________________________


23/301


24/301


25/301


26/301


27/301

Barretts EsophagusDysplasia: Definition Neoplastic epithelium that remains

confined within the basement membrane not reactive not synonymous with atypical unlikely to spontaneously regress

Both a marker and a precursor of adenocarcinoma


28/301

Barretts Dysplasia/CarcinomaRisk

Prevalence : 6-8%

Incidence : 0.2 3% (1/52 1/208 patient years)

Relative Risk: 30-125x


29/301

Incidence Rate of Adenocarcinoma inBarretts Esophagus

__________________________________________________________________

Incidence Follow-upSeries Patients Cases (Patient Incidence

(No.) (No) Years) Rate __________________________________________________________________

Haammeeteman et al 50 5 260 1/52Bonelli et al 71 2 110 1/55Roberston et al 56 4 224 1/56Miros et al 81 3 289 1/96

Iftikhar et al 107 4 462 1/115Drewitz et al 170 4 834 1/208OConnor et al 136 2 570 1/285Sepchler et al 108 4 1037 1/259

Sharma et al 618 12 2546 1/212 _________________________________________________________________


30/301


31/301

Patient Characteristics __________________________________________________________________ Variable G ERD Barretts HGD/CA(N=2170) (N=1189) (N=131)

__________________________________________________________________ Male sex 98% 99% 99%Age (yr*) 59+13 61+11 63+10White ethnicity 76% 83% 89%

Ethanol Consumption 40% 37% 42%Smoking 34% 25% 27%Hiatal hernia 24% 65% 84%Hiatal hernia size (cm*) 0.4+1.1 2.4+1.9 3.5+2.3

Barretts length (cm*) 2.6+2.1 5.0+4.4 __________________________________________________________________

Avidan et al. Am J Gastroenterol 2002;97(8) 1930-1936


32/301

DysplasiaPathologic Features1. Gross - Flat

- Elevated (plaque, nodule, polyp)

2. Microscopic - Adenoma-like- Non-adenoma like


33/301

Dysplasia in the GI Tract

NegativeIndefinite

Positive (low, high)Intramucosal AdenoCa

Submucosal (Invasive) AdenoCa


34/301

Non-Recommended Terms

AtypiaAdenomatous Changes

Carcinoma in Situ


35/301


36/301


37/301


38/301


39/301


40/301


41/301


42/301


43/301


44/301


45/301


46/301


47/301


48/301


49/301


50/301


51/301


52/301


53/301


54/301


55/301


56/301


57/301


58/301


59/301


60/301


61/301


62/301


63/301


64/301


65/301

Barretts-related DysplasiaInterobserver Agreement __________________________________________

Category % agreement __________________________________________ HGD + IMC vs. others 85-87%

Negative vs. others 71-72% Negative + Ind vs. others 75-77% Neg vs. Ind/LGD vs. HGD/IMC 58-61% __________________________________________

Reid BJ et al. Hum Pathol 1988


66/301


67/301

Adjunctive TechniquesProliferation Markers

DNA content (aneuploidy)Telomerase

Genetic mutations (p53, p16, Kras, APC,B catenin)

Growth FactorsApoptosis InhibitorsCyclooxygenase 2


68/301

Natural History _____________________________________

Dysplasia (%) n Cancer (%) _____________________________________

None 382 9 (2)Low grade 72 5 (7)High grade 170 37 (22)

_____________________________________ Sampliner. Am J Gastroenterol 2002:97(8);1888-1895

E h t f


69/301

Esophagectomy for High-Grade Dysplasia __________________________________________

Series Unsuspected Carcinoma

__________________________________________ Edwards (1996) 8/11 (73%)

Heimiller (1996) 13/30 (43%)Cameron (1997) 2/19 (10.5%)Ferguson (1997) 8/15 (53%)

Falk (1997) 4/12 (33%)

Total 35/87 (40%)

_________________________________________


70/301

Management Controversial Varies between institutions Dependent on surveillance

techniques


71/301

ACG guidelines for Surveillance in Barretts esophagus:

(Sampliner et al, Am J Gastroenterol 97:1888,2002)

Chronic GERD Symptoms

Screening Endoscopy with Biopsies

Negative for dysplasia Low grade dysplasia High-grade dysplasiax2 endoscopies

Repeat endoscopy with biopsyExpert pathologist opinion

3 year surveillance Repeat x 1Focal Mucosal Multifocal

Annual surveillance irregularityUntil no dysplasia 3 months Intervention

surveillance EMR (surgical)


72/301

Ideal Biopsy Protocol Jumbo forceps 4 quadrant Q2 cm in BE

4 quadrant Q1 cm in dysplasia All nodules/polyps/masses

Confirm with experienced GI pathologist


73/301

Management ConsiderationsSurveillance vs. Esophagectomy

Extent of HGD NodularityPatient age

ComorbiditiesLength of BE


74/301

Barretts Esophagus: New Surveillance Strategies

Balloon cytology

Fluorescence spectroscopy Chromoendoscopy Flow cytometry


75/301

l l f


76/301

Molecular Basis of Barretts Esophagus

Stepwise genetic progressionSpecific factors

aneuploidy17p deletion/p53 mutation

p16cyclin D1

G ti P i


77/301

Genetic Progressionin Barretts Esophagus

Barretts LGD HGD AdenoCa

7p12 amplification/EGFRoverexpression

17q21 amplification/HER2overexpression

19q12 amplification/Cyclin E

overexpressionother amplifications (2p, 8q, 20q)chromosomal deletions (3p, 4p,

7q, 12q, 17q, 22q)

E and P cadherin loss

11q13 amplification/Cyclin D1overexpression

5q21 deletion/APC inactivation9p21 deletion/p16 inactivation13q14 deletion/Rb inactivation

17p13 deletion/p53 mutationp21 overexpressionp27 lossaneuploidy

telomerase overexpression

Non Dysplastic


78/301

Non-DysplasticBarretts Esophagus

Normal BEHigh Risk

BE

Dysplasia

Cancer

11q13 amplification/Cyclin D1overexpression

Bcl2 overexpression5q21 deletion/APC inactivation

9p21 deletion/p16 inactivation13q14 deletion/Rb inactivation17p13 deletion/p53 mutation

aneuploidy

A l id


79/301

Aneuploidy

Normal cells:

diploid (2N)tetraploid (4N; G2 phase)S phase cells

Gains or losses of entire chromosomes

Peaks of abnormal DNA contentAbnormally large tetraploid peaks

Aneuploidy Predicts Progression


80/301

Aneuploidy Predicts Progression

in Barretts EsophagusHistology Ploidy Dysplasia/CancerProgression

Negative diploidaneuploid/4N

2/1101/10

Indefinite diploidaneuploid/4N

1/721/11

LGD diploidaneuploid/4N

0/334/11

Total diploidaneuploid/4N

3/2156/32

Reid et al, Am J Gastroenterol 95:1669;2000

Tumor Suppressor Genes


81/301

Tumor Suppressor Genes

Cellular brakes or checkpoints

OFF signal

Inhibit cell growth

Regulate cell division


82/301

p53 Gene Detection

17p loss of heterozygosity (LOH)p53 gene mutationSSCPsequencing

p53 gene immunostainingmutations stabilize expression

53 G M t ti i


83/301

p53 Gene Mutations inBarretts Esophagus

Frequency:negative 5%indefinite 5%LGD 20%

HGD 60%Mucosa beside positive dysplasia

17p LOH & Progression


84/301

17p LOH & Progression

in Barretts NeoplasiaHistology Alteration Progression Relative Risk

Neg/Indef/LGD 17p intact 16/178 (9%)

17p LOH 5/19 (26%) RR 3.6

HGD 17p intact 5/24 (21%)

17p LOH 18/35 (51%) RR 3.0

Reid et al, Am J Gastroenterol 96:2839;2001

p53 Immunostain & Progression


85/301

p53 Immunostain & Progression

in Barretts NeoplasiaStudy p53

ImmunostainProgression From

Indefinite/LGD

Younes 1997 negative

positive

0/16 (0%)

5/9 (55%)

Bani-Hani 2000 negativepositive

7/41 (17%)4/11 (36%)

Weston 2001 negativepositive

2/25 (8%)3/6 (50%)

p53 Positive Immunostaining


86/301




87/301


p53 Positive Barretts Indefinite


88/301

p53 Positive Barrett s Indefinite


89/301

p16/INK4a/CDKN2A Gene

Regulation of cell cycleG1 phase

Binds Cdk4Competes with Cyclin D1

Inhibits phosphorylation of RbInduces growth arrest


90/301

Detection of p16 Inactivationin Barretts Esophagus

9p21 deletion (LOH)

Promoter CpG island methylationp16 mutationLoss of p16 immunostaining

16 I i i


91/301

p16 Inactivationin Barretts Esophagus

Common early eventLarge non-dysplastic fields>85% of dysplasiasPrecedes aneuploidy/17p LOHNot characterized as risk factor

C li D1 G


92/301

Cyclin D1 Gene

Cyclin/CDK complexesRegulation of cell cycle

G1 phaseCyclin D1/Cdk4,6

Phosphorylation of RbProgression through cell cycle

Cyclin D1 and Progression


93/301

Cyclin D1 and Progressionin Barretts Neoplasia

Bani-Hani JNCI 92:1316;2001Case-control studyCyclin D1 positive immunostain

8/12 adenocarcinoma group14/49 control group

Odds ratio 6.85

M l l S f


94/301

Molecular Summary of Barretts Esophagus

Non-dysplastic genetic changes

Stratify progression in negative,

indefinite, and LGD

M l l S f


95/301

Molecular Summary of Barretts Esophagus

Useful predictive factors:

aneuploidy/4N fraction17p deletion/p53 inactivationCyclin D1 expression


96/301


97/301

Dysplasia in IBD

Dysplasia in Crohns ColitisDysplasia in Ulcerative Colitis

General commentsRisk factors

Treatment/surveillance DALMs in Ulcerative Colitis

Non IBD-dysplasia


98/301

Dysplasia in Crohns Disease Risk of Colon Cancer Similar to UC

Involved (SI and colon) anduninvolved areas

Dysplasia-carcinoma sequence Dysplasia morphologically similar

to UC Endoscopic surveillance controversial


99/301

Dysplasia in Crohns DiseaseDysplasia-Carcinoma Sequence

Dysplasia adjacent to Ca in 40-100%

More common close to tumor 2-16% of patients without carcinoma


100/301

Dysplasia in Crohns Disease(Sigel et al, Am J Surg Pathol 23:651,1999)

30 Cases Crohns Adenocarcinoma 27% SI, 73% colon (all involved)

Dysplasia adjacent to Ca: 87% Dysplasia distant to Ca: 41%

(75% in UC)


101/301

Dysplasia in Ulcerative Colitis Unequivocal neoplastic epithelium

Marker of malignancy risk

Present in 90% (close and distant) of carcinomas

Any portion of colon (parallels cancer)- single, multiple, diffuse

Flat or elevated (DALM)


102/301

Risk of Neoplasia in UC1. Dysplasia

5% incidence/10 years 25% incidence/20 years

2. Carcinoma 3-43% incidence 25-35 years- 5-10% incidence/20 years- 10-20% incidence/30 years

1-2%/year after 10 years

D l i /C i Ul i C li i


103/301

Dysplasia/Ca in Ulcerative ColitisRisk Factors

Disease duration (> 10 years) Disease extent Primary sclerosing cholangitis Disease severity Early age of onset? Family history of colon cancer? Folate deficiency?

P i S l i Ch l i i


104/301

Primary Sclerosing CholangitisRisk of Dysplasia

(Marchesa et al, Am J Gastro 1997;92:1285)

27 pts with UC and PSC

1185 pts with UC only all had total proctocolectomy

60% vs 12% dysplasia Rt colon dysplasia/carcinoma


105/301

Dysplasia in UC

Gross Features

Flat Raised (DALM)


106/301


107/301


108/301


109/301


110/301


111/301


112/301


113/301


114/301


115/301


116/301


117/301


118/301


119/301


120/301


121/301


122/301


123/301


124/301


125/301


126/301


127/301


128/301

UC-Associated Dysplasia


129/301

UC Associated DysplasiaInterobserver Variability

_______________________________________________

Author # Specimens #Pathologist K value_______________________________________________ Odze (2001) 38 4 0.4Melville (1990) 207 5 0.2-0.5Dixon (1988) 100 6 (pairs) 0.4

_______________________________________________

Risk of Malignancy in UC


130/301

Risk of Malignancy in UCAdjunctive Methods

Histochemical .. mucin, sialosyn TN Impox ... proliferation Molecular defects . P53, Rb, APC, MI,

CIN, P27,P16,

aneuploidy Laser fluorescence dysplasia

Flat Dysplasia


131/301

Natural History(Bernstein et al, Lancet 1994;343:71)

1. Low grade- Co-existant carcinoma: 9%

- Progression to HGD/CA: 30-54%(5 year predictive value )

2. High grade- Co-existent carcinoma: 40-67%- Progression to CA: 40-90%

(2-5 year predictive value)


132/301

ManagementDysplasia

Low grade High grade

Unifocal Multifocal Synchronous

Surveillance Colectomy Colectomy? Colectomy


133/301

Colectomy for Low Grade Dysplasia_______________________________________________

Author Data_______________________________________________ Connell 1994 LGD to HGD (54%, 5 years)

Taylor 1992 LGD in CA colectomy (34%)Bernstein 1994 CA in LGD colectomy (19%)Woolrich 1992 LGD to CA (18%, 6 years)_______________________________________________


134/301

DALM1. Adenoma-like- Sporadic (Adenoma)

- IBD-associated(Polypoid dysplasia)

2 . Non Adenoma-like


135/301

DALM Adenoma Like

Sessile/Pedunculatedwell circumscribedsmooth surfacevisible bordersnon-ulceratedno stricture or mucosaltethering

Non Adenoma-LikeUsually sessilePoorly circumscribedIrregular surfaceindistinct border ulceration/necrosis+stricture/tethering


136/301


137/301


138/301


139/301

Summary of DALM Studies_______________________________________________

Author #Patients % DALM % DALMwith cancer

_______________________________________________

Blackstone (1981) 112 11% 58%Butt (1983) 62 29% 83%Rosenstock (1985) 248 5% 38%

Len-Jones (1990) 401 1.5% 83%Bernstein (1994) 1225 3.2% 43%(10 studies)

_______________________________________________


140/301

Adenoma vs Polypoid Dysplasia

1. Morphology

2. Immunohistochemistry3. Molecular defects


141/301

Polypoid Dysplasia and

Adenomas in InflammatoryBowl DiseaseTorres, Antonioli, Odze

Am J Surg Pathol 1998;22(3):275-284


142/301


143/301


144/301


145/301


146/301

Adenoma vs Polypoid DysplasiaValue of Impox

Adenoma: catenin, Bcl-2

Polypoid Dysplasia: P53 Non sensitive and non-specific


147/301

IBD vs Sporadic Neoplasia_______________________________________________ IBD Sporadic

GENE Neoplasia Neoplasia ________________________________________________________ Kras early, frequent early, frequentP53 (17P) early, (44%) late (20%)

LOH 17P early, (85%) Late (20-30%)LOH 9P (P16) early, (50%) RareLOH 3P (50%) early, (50%) Rare, lateAPC (5q) late (6%) early (75%)P27 early, (90%) late (30%)

________________________________________________________

Genetic Alterations in


148/301

Chronic ulcerative colitis-

associated adenoma likeDALMS are similar to

non-colitic sporadic

adenomas

Odze et al, am J Surg Pathol 2000;24(9

Adenoma-like DALMS in UlcerativeColitis


149/301

___________________________________________________________ __ CUC Adenoma CUC

-like DALM non-adenoma

Molecular Non-CUC within outside like DALMMarker Adenoma Colitis Colitis (LOH)

n = 23 n = 10 n = 11 n= 12

___________________________________________________________ __

3P 5% 30% 25% 50%* 1

APC 33% 29% 38% 43%

P16 4% 0% 10% 56%*2

___________________________________________________________ __ *1P=0.01 * 2P = 0.003


150/301

Is it possible to reliablydifferentiate adenoma from

polypoid dysplasia by

morphology, impox, or molecular methods?

No.


151/301

Polypectomy may be adequatetreatment for adenoma-likedysplastic lesions in chronic

ulcerative colitisEngelsqjerd, Farraye, Odze

(Gastroenterology 1999;117:1288-1294)

______ Feature CUC patients Non-CUC

Adenoma-like AdenomaAdenoma


152/301

AdenomaDALM

__________________________________________________________________ ______

# patients 24 1049

Follow-up (mths) 42 4137

Flat dysplasia 1 (4%) 0 (0%)

NA New polyps 58% 50%

39%Adenocarcinoma 0% 0%


153/301


154/301

Rubin et al________________________________________

No further polyps 25 (52%)Polyps in same vicinity 13 (27%)

Polyps in different location 10 (21%)Dysplasia/CA in flat mucosa 0 (0%)________________________________________


155/301

ConclusionIf it looks like an

adenomaIt probably is!

DALM


156/301

Adenoma-like Non-Adenoma-like(broad-base, irregular)

Outside colitis Inside colitis

Polypectomy Polypectomy Colectomy

Regular surveillance Confirm absenceof flat dysplasia? Increase

surveillance


157/301


158/301

Molecular Basis of


159/301

Colitis-Associated NeoplasiaStepwise genetic progressionSporadic vs colitis-associated

Specific factorsaneuploidy

17p deletion/p53 mutationp16

Genomic instability pathways


160/301


161/301

Normal Negative/Indefinite High RiskDysplasia/

Cancer

aneuploidy17p13 deletion/p53 mutation

9p21 deletion/p16 inactivationchromosomal instability

Genetic Progression inColitis-Associated Neoplasia

Colitis-Associated


162/301

Versus Sporadic NeoplasiaAneuploidy pre-invasionp53 mutation pre-invasion

Chromosome 3p deletionLoss of p27 expression

Less bcl-2 expression

Less beta-catenin staining


163/301

Aneuploidy Associations in


164/301

Colitis-Associated Neoplasia

Associated with:durationextentseveritydysplasiaother genetic alterations

neuploidy Predicts Progressionin Colitis-Associated Neoplasia


165/301

p

Histology Ploidy Dysplasia/Cancer

ProgressionNegative diploid 0/15

aneuploid 1/1

Indefinite diploid 1/5

aneuploid 4/4

Rubin et al, Gastroenterology 103:1611;1992

neuploidy Predicts Progressionin Non-Dysplastic Colitis


166/301

Study Ploidy Dysplasia/Cancer

ProgressionLindberg 1999 diploid 0/127

aneuploid 4/10

Holzman 2001 diploid 1/39

aneuploid 5/10

17p LOH in


167/301

Colitis-Associated Neoplasia __________________________________________ ______

LesionFrequency

__________________________________________ ______

Carcinoma 22/26(85%)

HGD 25/4063%

p53 inNegative/


168/301

IndefiniteMucosa


169/301

Other Markers in


170/301


Proliferation index (Ki67)Cyclin A

E-cadherinSialosyl-Tn antigen

MetallothioneinFurther studies needed to validate

Chromosomal Instability by FISH


171/301

ArmDeletion

ArmAmplification

ChromosomeGain

ChromosomeLoss

Centromere probeChromosome arm probe Normal

Chromosomal Instability (CIN)


172/301

in Colitis-Associated Neoplasia

Dual color FISH chromosomes 8, 11, 17, 18Histologically negative rectal biopsiesCIN present in:

10% non-IBD control cells22% negative colitis cells (dysplasia orcancer elsewhere)

P


173/301


Cap on ends of chromosomesMaintain genome stability

Loss associated with senescenceAccelerated shortening with:

rapid cell turnoveroxidative injury

Telomere Erosion in


174/301


OSullivan et al, Nature Genetics 2002Determined telomere length innon-dysplastic mucosa by FISH

Patients with and without HGD/cancer

Telomere erosion associated with:chromosomal instabilityprogression to HGD/cancer)

Fecal DNA Mutation Testing


175/301

Cells shed into lumen

Target DNA by hybridcapture

Test specific mutationpanel

Krasp53APC

DNA integrity

Fecal DNA Mutation Testing


176/301

High sensitivity/specificity inCRC

Adenoma validation ongoing

Testing required on colitis

Development of cost-effective kit

Molecular Summary of


177/301

Useful predictive factors:

Aneuploidy17p deletion/p53 inactivation

Chromosomal instabilityTelomere erosion



178/301

Squamous Dysplasia


179/301

Esophageal squamous dysplasia General comments Clinical features Pathologic features Differential diagnosis Natural history, treatment

Squamous dysplasia

l l f


180/301

clinical features Similar risk factors as squamous cell

carcinoma (tobacco, alcohol, nutritionalfactors, hot beverages, chronic esophagitis,?HPV)

More common in high incidence areas of squamous cell carcinoma

Dysplasia frequently (up to 60%) adjacentto invasive carcinoma

Esophageal squamous dysplasia

l f


181/301

ClassificationCurrent/WHO

Negative

Low grade

High grade

Previous

Negative

Mild Moderate

Severe Carcinoma in situ

h l f


182/301

Pathologic features Gross: erythematous, irregular, friable;

erosions, plaques, nodules; may be normal Location: mid-distal esophagus (similar to

SCC) Lugols iodine

Baloon cytology in high risk areas


183/301


184/301


185/301


186/301


187/301


188/301


189/301


190/301


191/301

Squamous dysplasia- differential

di i


192/301

diagnosis Reactive squamous epithelium Giant cell esophagitis Chemoradiotherapy effect Invasive squamous cell carcinoma


193/301


194/301


195/301


196/301


197/301


198/301


199/301


200/301


201/301


202/301


203/301


204/301


205/301


206/301


207/301

Squamous dysplasia

Natural history


208/301

Natural history

60-708 yrs30%High grade

2-168-15 yrs15%Low grade

RR of

carcinoma

IntervalProgressDiagnosis

Increased risk for developing carcinomaMust exclude adjacent carcinoma

Squamous dysplasia- treatment


209/301

DYSPLASIA

FLAT

HIGHGRADE

ELEVATED

RESECTION

PROBABLECARCINOMA

FOLLOW

LOWGRADE

REBIOPSY

Molecular Basis of Squamous

Dysplasia of Esophagus


210/301

Dysplasia of Esophagus

Stepwise genetic progression

Specific factorsp53 mutation


211/301

P53 immunostain


212/301

Normal Dysplasia

p53 Immunostaining in

Esophageal Squamous Neoplasia


213/301

Fagundes Dis Esophagus 2001Esophageal Squamous Neoplasia

2/2 (100%)HGD

4/11 (36%)LGD1/3 (33%)Severe esophagitis

4/18 (22%)Moderate esophagitis6/43 (14%)Mild esophagitis

12/103 (12%) Normal p53 positivityCondition

Molecular Summary of

Esophageal Squamous Neoplasia


214/301

Esophageal Squamous NeoplasiaPredictive markers possible

p53 immunostaining

Many further studies required

(New Technologies)


215/301

Small Intestinal Metaplasia andDysplasia

Small intestine

metaplasia and heterotopia


216/301

metaplasia and heterotopia Gastric mucous cell metaplasia Pyloric gland metaplasia Gastric heterotopia

Pancreatic heterotopia


217/301


218/301


219/301


220/301


221/301

Pyloric gland metaplasia


222/301

Marker of chronic mucosal injury in small

intestine (e.g. Crohns disease) Up to 22% of Crohns patients

Most common in ileum Usually incidental finding

May form visible mucosal nodule


223/301


224/301

Small intestinal dysplasia


225/301

Crohns disease-associated dysplasia

Sporadic adenomas Polyposis-associated dysplasia

FAP Peutz-Jeghers syndrome

Other polyposis syndromes

Crohns disease-associated

dysplasia


226/301

dysplasia 5% lifetime risk of carcinoma

median disease duration 15 years Most (70%) are in colon, rectum

20-100X risk of small intestinaladenocarcinoma

Dysplasia-carcinoma sequence appearssimilar to colon


227/301


228/301


229/301


230/301


231/301


232/301


233/301


234/301

Gastric Metaplasia and Dysplasia

Intestinal-type gastric carcinoma-

a multistep process


235/301

Normal Chronic (active) gastritis

Chronic atrophic gastritis

Intestinal metaplasia

Dysplasia

Carcinoma

Gastric carcinomarisk factors


236/301

H. pylori gastritis

Autoimmne gastritis/pernicious anemia Post-gastrectomy

Gastric polyps Diet, environmental factors

(Cardia tumors: ?reflux)

Types of gastric epithelial

metaplasia


237/301

p Intestinal

Pseudopyloric

Ciliated

(Pancreatic: actually a heterotopia?)


238/301


239/301


240/301


241/301


242/301


243/301


244/301

Gastric dysplasia- issues


245/301

Different grading systems

Regeneration vs true dysplasia

Significance of mild dysplasia

High grade dysplasia vs adenocarcinoma

Gastric dysplasia

Padova classification Negative for dysplasial


246/301

Normal Reactive foveolar hyperplasia Intestinal metaplasia (IM)

Indefinite for dysplasia Foveolar hyperproliferation

Hyperproliferative IM

Non-invasive neoplasia low-grade dysplasia

high grade dysplasia

Suspicious for invasive carcinoma Invasive carcinoma

Gastric dysplasia

Japanese classificationCATEGORY DEFINITION HISTOLOGIC EQUIVALENT


247/301

CATEGORY DEFINITION HISTOLOGIC EQUIVALENT

Group I Normal/no atypiaNormal, regenerative,hyperplastic, intestinal metaplasia

Group IIAtypia butdiagnosedas benign

Regenerative with atypia (us.Architectural) due toinflammation

Group III Borderline betweenbenign & malignantDysplasia (flat and adenoma)?low grade ?high grade

Group IV Strongly suspectedof carcinoma High grade dysplasia?

Group V Carcinoma Invasive carcinoma.High grade dysplasia?

Adapted from Rugge M AJSP 24:167 (2000)


248/301


249/301


250/301


251/301


252/301


253/301


254/301


255/301


256/301


257/301

Gastric dysplasia-differential

diagnosisR i i h li dj l


258/301

Reactive epithelium adjacent to ulcer

Reactive (chemical) gastropathy Treatment effect

Invasive carcinoma


259/301


260/301


261/301


262/301


263/301


264/301


265/301


266/301


267/301


268/301


269/301


270/301


271/301

Gastric dysplasia- natural historyN Median

timeProgress

t CAPersistRegressStarting

D


272/301

3

16

90

9

3033%67%0%Suspicious

3069%25%6%High grade

489%38%53%Low grade

---0%11%89%Indefinite

time(mos)

to CADx

Rugge et al Gut 52:1111 (2003)

Gastric Dysplasia

ManagementLOW GRADE HIGH GRADE


273/301

LOW GRADE

SURVEILLANCE

MASSNO MASS

HIGH GRADE

REBIOPSY,CONSIDER RESECTION

REBIOPSY,CLOSE

FOLLOWUP

Gastric polypsNon-neoplastic Dysplasia?


274/301

Hyperplastic rare Fundic gland polyp Sporadic -

FAP-associated + Other polyposis rare

(juvenile, Cowdens)Neoplastic Adenoma ++

Gastric hyperplastic polyps

Most common gastric polyp


275/301

Most common gastric polyp

Prevalence 0.1% More common a/w gastritis

Gross: antrum>fundus, cardia; avergae 1.0cm


276/301


277/301

Dysplasia in hyperplastic polyps

Intestinal metaplasia in 15-25%


278/301

Intestinal metaplasia in 15 25%

Dysplasia in 2-19% Carcinoma in 0-17% (average 2%)

Dysplasia more common in larger (>2 cm) pedunculated polyps with intestinalizedepithelium


279/301


280/301


281/301


282/301

Fundic gland polyps

Clinical features Hamartomatous polypS di 0 1 1% l F M iddl


283/301

Sporadic: 0.1-1% prevalence, F>M, middleaged, 40% multiple

Association with PPI therapy

FAP: present in 50-100% of patients, >90%multiple


284/301

Dysplasia in fundic gland polyps

Sporadic:


285/301

Sporadic: 1%

FAP: 25%

Usually low grade Relationship to gastric carcinoma?


286/301


287/301

Molecular Basis of

Gastric Dysplasia


288/301

Stepwise genetic progressionSpecific factors

p53MLH1

APCFundic gland polyps

Genetic Progression

in Gastric NeoplasiaC-met/HGF amplification/


289/301

Normal Metaplasia Dysplasia AdenoCa

poverexpression

9p21 deletion/p16 inactivation19q12 amplification/Cyclin E

overexpression18q deletion16q22 deletion/E-cadherin losschromosomal deletions (1p, 1q,

7q, 13q)

5q21 deletion/APC inactivation17p13 deletion/p53 mutationMLH1 methylation

p53 Alterations in Gastric

Metaplasia and Dysplasia


290/301

Shiao Am J Pathol 199412 resectionsp53 immunostaining/mutationsmetaplasia 38%dysplasia 58%carcinoma 67%

i h i d f

Microsatellite Instability in

Gastric Adenocarcinoma


291/301

Mismatch repair gene defectMicrosatellite instabilityPresent in 15-25% gastric CaRarely germline (HNPCC)Most caused by:

MLH1 methylationLoss of MLH1 expression

M L H 1

M S H 2 MS H 3

DNA mismatch

mismatch binding


292/301

PM S 1

Modified from Fishel et alCancer Research 61:7369;2001

M S H 2 M

S H 3

M L H 1 P M S 1

M S H 2 M

S H 3

conformation change

recruit partners

Immunohistochemistry 6 X 6 micron

R i d k lid

Analysis of DNA MismatchRepair From Tumours


293/301

B r i gh am

an d

W om en s

TN

H&E X1

Unstained 10 X 10 micron

Review and mark slide

for dissection

Overlay on H&E and scrape tissue from unstained

Extract DNA for MSI testing

B r i gh am

an d

W om en s

Mismatch Repair Gene Immunohistochemistry


294/301

MLH1

MLH1

MSH2

MSH2

Microsatellite Instability in

Gastric Metaplasia/Dysplasia


295/301

Leung Am J Pathol 2000

MSI in 7/75 (9%) intestinalmetaplasia

Associated with MSI cancers

MLH1 Methylation inGastric Metaplasia/Dysplasia


296/301

Kang Canc Res 2001

MLH1 methylation in:chronic gastritis 0%intestinal metaplasia 6%

adenoma 10%carcinoma 20%

Kang Canc Res 2001

CpG Island Methylation inGastric Metaplasia/Dysplasia


297/301

Kang Canc Res 2001

p16, THBS1, TIMP3

CpG island methylation in:chronic gastritis 0-15%intestinal metaplasia 2-36%adenoma 11-27%carcinoma 42-57%

Occur in two settings

Fundic Gland Polyps


298/301

g

Familial Adenomatous Polyposis

Occasionally have epithelial dysplasia

SporadicRarely have dysplasia

AX

WNT

Frizzled

Dvl

APC in

WNTSignaling


299/301

X

IN

APC-catenin

-catenin

-catenin

GSK3 P

C-Mycand othersLEF1

Genetic Predictors of Dysplasiain Fundic Gland Polyps


300/301

APC mutation associated with dysplasiaFAP-associated FGPsrare sporadic FGPs

Beta-catenin mutation not dysplastic

most sporadic FGPs

Molecular Summary of Gastric Dysplasia

Predictive markers possible


301/301

pPromising markers:

p53 immunostaining

MLH1/other gene methylation

pre zen tare pe esofag baret

Documents